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Chapter 5
The Impact of Adjuvanted and Non-Adjuvanted
Influenza Vaccines on the Innate and Adaptive
Immunity Effectors
Mikhail Petrovich Kostinov,
Nelli Kimovna Akhmatova,
Ekaterina Alexandrovna Khromova,
Svetlana Anatolyevna Skhodova,
Vera Nikolaevna Stolpnikova,
Alexander Petrovich Cherdantsev and
Anna Egorovna Vlasenko
Additional information is available at the end of the chapter
http://dx.doi.org/10.5772/intechopen.77006
© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons
Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use,
distribution, and reproduction in any medium, provided the original work is properly cited.
Inluenza Vaccines on the Innate and Adaptive
Immunity Efectors
Mikhail PetrovichKostinov,
NelliKimovnaAkhmatova,
EkaterinaAlexandrovnaKhromova,
Svetlana AnatolyevnaSkhodova,
VeraNikolaevnaStolpnikova,
Alexander PetrovichCherdantsev and
Anna EgorovnaVlasenko
Additional information is available at the end of the chapter
Abstract
-
bodies formation is proved. However, cellular mechanisms, including parameters of
the innate immunity, involved in the vaccine-induced immune response are not well
studied. The human study of inactivated vaccines showed that both subunit vaccine
and split vaccine induced cellular immune response, but adjuvanted vaccine containing
can trigger intracellular signals leading to the induction of antiviral mechanisms and to
the activation of the body’s protective resources against microbial infections. To assess the
necessary to evaluate activation of cellular mechanisms of innate and adaptive immunity.
Keywords:
subpopulations, toll-like receptors
© 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative
Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use,
distribution, and reproduction in any medium, provided the original work is properly cited.
1. Introduction
inactivated (whole-virion, split-virion and subunit) vaccines. Currently, inactivated split and
domain of hemagglutinin protein and neuraminidase protein of contemporary serotypes of
enough for certain categories of vaccinated people [1–7]. Some of them are not able to protect
8–11].
great interest [12
-
of vaccines meant to activate all the components of the immune system. According to the
-
vate of not only adaptive, but also innate immunity, have been conducted. In addition, unlike
-
ratory infections in the postvaccinal period [13–15].
16], and must meet at least one of the three
criteria:
• seroconversion (percentage of subjects with a fourfold increase in antibody titers after vac-
• seroprotection (percentage of subjects with a protective antibody titers before and
• multiplicity factor for the increase of antibody titers compared to baseline—at least 2.5.
Taking into account a new type of vaccine (adjuvanted), not only humoral, but also cellular
of cellular immunity parameters, important to the formation of immunological memory, may
Influenza - Therapeutics and Challenges84
the number of cells with toll-like receptor expression in vitro.
2. Materials and methods
2.1. Clinical characteristics of patients
-
previous 6 months.
2.2. Legal basis of the study
Once the signed informed consent for study participation was obtained, venous blood
in vitro in healthy
USA), using anti-CD45/CD3, anti-CD45/CD3/CD4, anti-CD45/CD3/CD8, anti-CD16/56, anti-CD3/
2.4. Toll-like receptors
-
6
corresponding vaccine for 72 hours.
2.5. Study vaccines
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-
baseline serum
antibody levels
HAI assay. The 4+ system was applied to HAI assay: an antigen titer, i.e., 1 HAU, was highest
2.6. Statistical analysis
-
17
was used to account for multiple comparison (false discovery rate control) [18]. The obtained
3. Study results
infection in the unvaccinated volunteers could have been masked under the guise of another
and activated cells (Table 1).
Figure 1). It should be
-
cyte number except subunit vaccine, which caused a decrease in the percent of T lympho-
not change. These results may indicate a shift in the number of cells due to an increase in the
number of other subpopulations.
Influenza - Therapeutics and Challenges86
Lymphocyte
subpopulations
N % in comparison groups – Me(Q1–Q3) F p q
Control Subunit
V
Adjuvanted
V
Split-
product V
T lymphocytes
18
(74.17–
83.35)
71.25
(64.7–
74.6
78.22)
Helper T cells
21 43.5
37.5
(32.7–
43.8)
(31.8–46.5)
(35.6–47.7)
Cytotoxic
21 23.5
(17.3–24.7)
21.2
(17.4–
23.6)
22.5
21.5
(18.4–5.8)
(CD16/56+)
24 4.85
13.2
(11.15–
14.85)
17.25
15
(13.8–16.25)
(CD3/CD16/56+)
24 1.6
(1.3–2.25)
3.6
(2.775–
5.825)
7.5
(6.675–8.225)
5
(4.625–6.75)
57.52
24 5.15
(4.475–
6.725)
16.36
(15.47–
17.7)
21.15
18.1
(15.88–
167.44
Activated
cytotoxic
T lymphocytes,
1.6
(1.2–2.4)
1.35
13.36
Activated
T lymphocytes
12
2.7
(1.875–
3.375)
(3.775–7.1)
2.6
Activated
lymphocytes
(CD45/CD25+)
16 1.45
(1–1.775)
3.7
(2.6–4.85)
4.15
4.15
5.275)
Tregs
13 2.7
3.5
3.7
(3.2–5.5)
4.2
(2.2–4.5)
4.27
(CD4/CD8)
1.825
(1.5–3.275)
1.85
(1.45–
2.325)
1.85
(1.4–2.5)
1.65
(1.475–.525)
1.26
6
2
Table 1.
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Figure 1-
Figure 2).
Figure 1.
Figure 2.
Influenza - Therapeutics and Challenges88
Table 1, Figure 1).
-
-
ferent types of vaccines were observed in all groups of volunteers, regardless of the baseline
Figure 2).In women
-
-
responds to a 2.6- to 3.6-fold increase. Immunoadjuvant-containing vaccine produced more
-
ences between various types of vaccines.
-
3.1-fold increase compared to control (Table 1, Figure 1).
Figure 2).
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89
higher after in vitro
-
-
Table 1, Figure 1).
Figure 2
-
compared to control. Immunoadjuvant-containing vaccine had the greatest potential for
-
-
Table 1, Figure 1).
Influenza - Therapeutics and Challenges90
However, changes in the number of activated cytotoxic T lymphocytes in vitro between vac-
Figure 2
Table 1, Figure 1
Figure 2
-
Figure 2).
-
Table 1, Figure 1).All types of vaccines increased number
Figure 2).
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Table 1, Figure 1). Immunoadjuvant-containing
Figure 2
Table 2.
Table 2, Figure 3 -
-
between vaccine types.
Figure 4
TLR N TLR-expressing granulocytes, %, Me (Q1-Q3) F p q
Control Subunit Adjuvanted Split
2 24 16.6
(14.2–18.38)
38.2
(37.73–42.4)
37.5
4 24 22.3
26.85
24.45
23.35
(21.5–25.35)
3 24
24.15
24
25.45 (24–26.32) 26.4
(24.48–28.23)
86.57
8 24
(18.68–22.4)
42.5 (37–45.1)
6 23
Table 2.
Influenza - Therapeutics and Challenges92
(phh
incubation with split vaccine (ph
fold for subunit and split vaccines (phh
compared with control.
after incubation with subunit vaccine (ph
vaccine (phh
control.
Table 2, Figure 3).
Figure 4) between vaccine types
number of these cells increased 1.1-fold after incubation with subunit vaccine compared to
control (ph
Figure 3.
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Table 2, Figure 3
expressing cells (Figure 4
-
tion with split vaccine (1.3-fold, phh
Analysis also revealed (Table 2, Figure 3
Figure 4). In women with
Figure 4.
Influenza - Therapeutics and Challenges94
h
-
h
ph h h
split vaccine caused 2.3- and 1.8-fold increase (ph h
Table 2, Figure 3). This receptor
-
Figure 4
induced 1.7-fold (phhh
hhh
increase, respectively, and split vaccine caused 1.8-fold (ph h
1.7-fold (ph
h
phhh
hh
hh
Table 2, Figure 3).
-
increased 1.5-fold after incubation with subunit vaccine, 1.3-fold after incubation with adju-
(Figure 4
fold (phh
1.2-fold (phh
1.3-fold (phh-
ber, respectively, compared to control.
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only after incubation with split vaccine (ph
4. Discussion
in certain patients [1–78–11]), there is a need
on the cellular and molecular immunologic mechanisms remains poorly studied.
-
in vitro.
tumor and virus-infected cells and to regulate innate and adaptive immune responses [, ].
reported to stimulate cellular immune response, regulate eosinophil maturation, and protect
respiratory epithelium [21]. When interacting with peripheral mononuclear cells, PO, a com-
normal limit or decreased [22].
23].
Cytotoxic T lymphocytes identify and kill virus-infected cells. Infected cells present virus
-
24, 25].
virus, but they can restrict virus reproduction and enhance virus elimination out of the body.
-
26, 27].
immune response, as recommended in WHO guidelines. We think that this assessment
Influenza - Therapeutics and Challenges96
is essential to also study the cellular immunity. Immunodominance, which means that the
immune system chooses one or more key epitopes for recognition, is an important factor for
the development of vaccines stimulating the cellular immune response [28]. Vaccines aimed
-
cantly narrow the cross-reactive range of immune response to various virus strains. The role
of antigen delivery route and presentation should also be considered when developing such
vaccines. To stimulate a strong cytotoxic immune response, an antigen should be processed
and presented by dendritic cells and coupled to MHC class I molecules. These may occur
either at the moment dendritic cells are being infected or transduced or when dendritic cells
engulf apoptotic bodies from other infected cells. Thus, the induction of cytotoxic immune
inactivated whole-virion and subunit vaccines) [21].
-
tributes to virion phagocytosis and to stimulation of antibody-dependent cellular cytotoxicity.
-
antibodies also stimulate antibody-dependent cellular cytotoxicity. In addition, anti-neuramini-
].
while no production of IgM antibodies was observed in secondary infection. IgM antibodies
21, ].
the body, and are indicative of recent virus exposure. Immunoglobulins G ensure the longest
21, ].
-
respectively. The studied vaccines were not found to activate other cell types.
-
of the best documented cell population. Increased Treg number can possibly be explained by the
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97
31, 32].
Innate immune mechanisms are key to protection against pathogens, since they ensure
33–36].
dendritic cells, which prepare the second line of immune response to the infection, known as
37, 38
immune response to infections caused by bacteria, fungi, and viruses [
known to be directly associated primarily with neutrophils, which express almost all identi-
accompanied by respiratory burst and changed expression of adhesion molecules [, 41].
gave the following results.
in vitro
-
non-stimulated cells.
Subunit vaccine
to be an important regulator of neutrophil survival [–42].
Split vaccine
generated during replication [43
to be accompanied by their activation, which allows them to get directly involved in various
types of immune response [44].
45, 46].
47].
Influenza - Therapeutics and Challenges98
infection—dendritic cells, both myeloid and lymphoid lineages [48
, ]. They
51].
Adjuvanted vaccine
45, 52]. The
of the adjuvant in the adjuvanted vaccine.
-
phocyte activation) [53
protective immune response to main antigens (hemagglutinin) [54].
-
the activation of both intracellular signaling systems. Thus, there are two important types
with interferon being the primary antiviral mediator in innate immunity [55].
5. Conclusion
well as induce humoral immune response. PO-containing adjuvanted vaccine showed the
strongest capability of inducing the cellular response, among the three vaccines studied.
in vitro
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defense mechanisms against microbial infection.
death of hundreds of thousands of people each year [56]. Complications leading to morbidity
and mortality following infection are predominantly observed in high-risk groups: children
of early age, people with chronic diseases and pregnant women [57]. According to WHO,
-
58].
-
of population groups - small children, pregnant women, the elderly, people with various
-
world, especially in the event of a pandemic [–61].
-
vants) have been proposed. With the use of adjuvants, it is possible to increase the immuno-
-
as well as reduce the dose of the antigen (hemagglutinin). This is especially important for
pre-pandemic vaccines, because with the same production capacity, more vaccines will be
, 61].
The action of most adjuvants is based on the prolongation of the AG action, which is provided
AG on certain carriers, the antigen is held in places necessary for exposure of the antigen to
immunostimulating complexes, an oil microemulsion [62].
63]. Adjuvants that
-
ing PO. Structural association of the AG and polymer-immunostimulant enhances the
migration of phagocytes, the functional activity of macrophages in tissues and increases
their processing activity [64].
Influenza - Therapeutics and Challenges100
The action of adjuvants depends on the initial immune status of the organism preceding the
vaccination. Adjuvants accelerate development and increase the level of immune response,
vaccination immunity is characteristic of adjuvanted vaccines. At the same time, a reliable
immune response is achieved with the help of small doses of AG and a small number of
injections of the vaccine [63].
does interact with three lymphocyte subclasses, predominantly binds with monocytes and
neutrophils and to a lesser extent with lymphocytes, enhancing intracellular H2O2 produc-
factor that is the participant of the cytokines synthesis regulation. The enhancement of the
similarly to that as it occurs in natural way [65].
-
noadjuvant in new generation vaccines and is a compound in subunit adjuvanted Grippol
Due to Polyoxidonium, all Grippol family vaccines contain 3-times lower antigen content in
Today Grippol vaccines are approved and especially recommended for vaccination of cohorts
that previously were considered to be not vaccinated (patients with allergic conditions, sub-
-
dren from 6 months of age, and pregnant women. These recommendations were made based
on relevant clinical trials results followed by many years practical mass vaccine application
experience [66, 67].
antibody response. In addition to the development of protective antibodies after vaccina-
tion, the induction of cell-mediated immunity is considered to be of critical importance [68].
strongly impaired, a T cell response against the vaccine was detected in most patients [].
why previous pandemics have emerged when new HAs have appeared in circulating human
T cell responses and needs to be combined with an adjuvant facilitating this response [].
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101
-
partially and predominantly suppressed after depletion of CD8+ and CD4+ T cells (induced
by intraperitoneal injection of the corresponding antibodies), respectively, suggesting that
CD4+ T cells predominantly and CD8+ T cells partially contribute to the protective immunity
71]. These results suggest that adjuvants
cross-presentation, and induces cell-mediated immune responses against antigen.
to ameliorate disease [72]. Activation of the parameters of innate immunity is critical for the
-
73].
promising task. Such universal vaccines are expected to contain both antibody production
immunity being involved. Adjuvants may play an important part, their functions being aimed
both at enhancing immune response to an antigen and at regulating that response [74]. Thus,
due to the emergence of a new type of vaccine (adjuvant), in assessing the immunological
Abbreviations
PO polyoxidonium
HAI hemagglutination inhibition
HAU hemagglutination unit
Influenza - Therapeutics and Challenges102
V Vaccine
MHC Major histocompatibility complex
HA hemagglutinin
nTreg natural thymus-derived regulatory cells
AG antigen
APC antigen-presenting cell
Author details
Mikhail Petrovich 1,2 Akhmatova1, Ekaterina Alexandrovna 1,
Svetlana Anatolyevna Skhodova1, Stolpnikova1,
Alexander Petrovich Cherdantsev3 and Anna Egorovna Vlasenko4
vaccinums@gmail.com
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103
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